Genes & Immunity

https://doi.org/10.1038/s41435-019-0066-z

REVIEW ARTICLE

The remarkable history of the hepatitis C virus

Stanislas Pol1,2,3,4,5 Sylvie Lagaye
●
4,5

Received: 28 February 2019 / Revised: 25 March 2019 / Accepted: 1 April 2019

© Springer Nature Limited 2019

Abstract
The infection with the hepatitis C virus (HCV) is an example of the translational research success. The reciprocal interactions
between clinicians and scientists have allowed in 30 years the initiation of empirical treatments by interferon, the discovery
of the virus, the development of serological and virological tools for diagnosis but also for prognosis (the non-invasive
biochemical or morphological fibrosis tests, the predictors of the specific immune response including genetic IL28B
polymorphisms). Finally, well-tolerated and effective treatments with oral antivirals inhibiting HCV non-structural viral
proteins involved in viral replication have been marketed this last decade, allowing the cure of all infected subjects. HCV
chronic infection, which is a public health issue, is a hepatic disease, which may lead to a cirrhosis and an hepatocellular
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carcinoma (HCC) but also a systemic disease with extra-hepatic manifestations either associated with a cryoglobulinemic
vasculitis or chronic inflammation. The HCV infection is the only chronic viral infection, which may be cured: the so-called
sustained virologic response, defined by undetectable HCV RNA 12 weeks after the end of the treatment, significantly
reduces the risk of morbidity and mortality associated with hepatic and extra-hepatic manifestations, which are mainly
reversible. The history of HCV ends with the pangenotypic efficacy of the multiple combinations, easy to use for
8–12 weeks with one to three pills per day and little problems of tolerance. This explains the short 30 years from the virus
discovery to the viral hepatitis elimination policy proposed by the World Health Organization (WHO) in 2016.

The hepatitis C virus (HCV) infection is an example of the
translational research success. The reciprocal interactions
between clinicians and scientists have allowed in 30 years
the initiation of empirical treatments by interferon, the
discovery of the virus, the development of serological
(ELISA, RIA) and virological (reverse transcriptase poly-
merase chain reaction or RT-PCR enabling the qualitative
and quantitative detection of viral RNA, genotyping,
resistance analysis such as basic virology) diagnostic tests
with an increasing sensitivity and specificity. In parallel,
* Stanislas Pol
stanislas.pol@aphp.fr
* Sylvie Lagaye
sylvie.lagaye@inserm.fr
1
Université Paris Descartes, Paris, France
2
Département d’Hépatologie, Hôpital Cochin, APHP, Paris, France
3
INSERM UMS-20, Institut Pasteur, Paris, France
4
Immunobiologie des Cellules Dendritiques, Institut Pasteur,
Paris, France
5
INSERM U1223, Institut Pasteur, Paris, France
non-invasive biochemical or morphological fibrosis tests,
predictors of the specific immune response including
genetic (IL28B) have been developed and finally, radically
effective treatments with HCV-specific oral antivirals inhi-
biting non-structural viral proteins involved in viral repli-
cation have been marketed this last decade, allowing the
cure of all infected subjects. The elimination agenda of the
World Health Organization (WHO) illustrates these major
advances but must not hide the global challenges of
tomorrow. If the diagnosis, efficacy, and tolerability of
treatment are no longer an issue, less than 1% of the 71
million infected individuals worldwide has been treated and
the majority of patients are unaware of their infection: the
next challenges are therefore mainly to improve the
screening and access to treatment for this frequent infection,
which represents a public health although that is the only
viral chronic infection that can be cured.
Epidemiology
Between 1990 and 2013, the viral hepatitis raised from the
tenth to seventh place worldwide as a cause of death today,
higher than the mortality from infection with human

immunodeficiency virus (HIV), malaria, and tuberculosis
[1]: the viral hepatitis appear as the leading cause of
infectious mortality in the world despite the HCV pre-
valence decreased from ~170 million chronic carriers
worldwide in 1999 [2] to 71 million in 2017 [3, 4]. This
reduction in prevalence is linked to reducing the risk of
nosocomial infection, improving access to an efficient
antiviral treatment (still a minority), but also to the mortality
of infected subjects. We now consider that 1% of the
world’s population is infected with HCV with over one
million seven hundred and fifty thousand new infections in
2015 mainly related to the parenteral risk, intravenous drug
use in the northern countries but also the lack of hemovi-
gilance in countries of intermediate or low economy [3, 4];
2.3 million people are co-infected with HIV and HCV.
There are major regional disparities in this prevalence since
the most exposed areas are Egypt or Mongolia with 15% of
the historically infected population. In these countries, the
contamination was mainly nosocomial due to the absence of
hemovigilance in Mongolia or due to the systematic treat-
ment of schistosomiasis without single-use equipment in
Egypt [5]. Other regions, such as West Africa or Central
Africa, are heavily infected with ~5–8% of the con-
taminated population, not only because of nosocomial
transmission but also because of certain “folkloric” prac-
tices (scarification, excision, cupping in Japan or barber in
Sicily). In northern countries, the prevalence of Hepatitis C
is less than 1% with a steady decrease in prevalence and
incidence over the past 20 years: as an example, in France,
the prevalence among insured persons decreased from 1.2%
in 1996 to 0.8% in 2011 and probably 0.47% in 2017 and
this decline is related to the high rate of the screening and
antiviral treatment and to the pro-active policy of harm
reduction especially among intravenous drug users (IVDU).
The overall mortality attributable to viral hepatitis in
2015 is ~720,000 deaths from cirrhosis and 470,000 deaths
from hepatocellular carcinoma (HCC) with an increase of
22% since 2000 [4]. Although the hepatitis B virus infection
mortality is almost twice as high, despite a vaccine that has
been available for more than 30 years, about 400,000
people die each year because of their chronic hepatitis C
infection, mainly because of cirrhosis (about 2/3) and also
because of hepatocellular carcinoma (1/3) [4].
The history of the hepatitis C virus
The history of HCV is unique in the history of micro-
biology, because its discovery was late, in 1988 occurring
after the first empiric therapeutic trials but later develop-
ments were extremely fast since in 30 years from HCV
isolation of the virus, the reciprocal interactions between the
S. Pol, S. Lagaye
research and the clinical field have led to the development
of reliable serological and virological diagnostic tests, the
development of effective treatments allowing to hope for
the cure of all the patients and the efficacy of HCV elim-
ination policies elimination programs [4].
This policy, promoted by the WHO and initiated by at
least 12 countries in the world, is not strictly speaking a
policy of elimination since it is expected a reduction of
new infections by 30% in 2020 and 90% in 2030 and a
reduction in hepatitis-related mortality of 10 and 65%,
respectively [4].
In 1988, Michael Houghton’s team isolated com-
plementary DNA from the blood of a person infected with a
“non-A non-B” virus, allowing the isolation of viral RNA
and the rapid development of serological diagnostic tests
[6]. Elisa tests (EIA) and radio-immunoassays (RIA, now
abandoned) were developed in parallel [6]; their sensitivity
and specificity are now excellent. The presence of anti-HCV
antibodies testified to the past exposure to HCV but did not
determine the active nature of the infection, suspected by
the presence of hypertransaminasemia but absent in a
quarter of chronically infected patients. The only limit of
the serology is the seroconversion time of about 4–10 weeks
after contamination compared to HCV viremia, which is
detectable by RT-PCR within 4 days post-infection.
The detection of HCV RNA by RT-PCR (and in parti-
cular of the negative strand) allows itself to assert the active
nature of the infection. The detection thresholds have been
lowered over the past 20 years and are now around 1.2 log,
i.e 12 IU/mL. HCV RNA is detectable in the liver [7] or in
the peripheral blood mononuclear cells and, of course, in
the serum where it is classically sought to affirm the active
infection. The isolation of the HCV RNA allowed the
sequencing of the virus and the definition of different
genotypes (numbered from 1 to 7) and subtypes (a, b, c…)
[8]. Quantitative tests of viremia have been developed,
allowing, for a given patient, the quantification and geno-
typic identification, at first, conditioning the therapeutic
choices and the duration of treatment in the interferon era
and enabling communities to trace contaminations and
migrations.
Prior to identification of HCV RNA [6], standard Inter-
feron therapies for non-A non-B hepatitis began in the late
80's (Fig. 1) [9]. It had been shown that 3–5 million Interferon
units, 5 days a week or every 2 days for 24, 48 or 72 weeks
allowed a viral eradication or sustained virological response
(RVS) defined by undetectable HCV-RNA within 24 weeks
after the end of treatment and corresponding to virological
cure [9]. In parallel to the standard virological tests, a ser-
ological identification of the HCV capsid antigen has been
developed; this test, which has a comparable sensitivity to
HCV-RNA quantification, has not experience the expected
The remarkable history of the hepatitis C virus
Fig. 1 Summary of the hepatitis C virus history and the antiviral
treatments against the Hepatitis C virus infection. IFN = Interferon;
RBV = Ribavirin; the protease inhibitors are in red (TVR = Telapre-
vir; BOC = Boceprevir; SMV = Simeprevir; PTV/r = Paritaprevir
boosted by ritonavir; GZR = Grazoprevir; G = Glecaprevir; VOX =
developments but could be a less expensive and as effective
test as the viral load quantification.
The development of the serological tests allowed on the
one hand the identification of the subjects having met the
HCV (presence of anti-HCV antibodies) and the detection
of the HCV RNA by RT-PCR in the serum the identifica-
tion of the subjects having an active infection. Thus a
patient with anti-HCV antibodies and undetectable HCV
RNA is a patient exposed but cured of his infection. Ser-
ological tests allowed for a mass screening including blood
donors. After the identification of hepatitis B virus markers
(anti-HBc or HBs antigen) leading to the exclusion of blood
donation, the identification of anti-HCV antibodies reduced
the risk of “transfusion” contamination by HCV related to
blood products (blood, immunoglobulins, anti-hemophilic
factors, fresh frozen plasma, etc.). Before this screening, the
risks were approximately 5 to 10% per transfused blood
pellet; they are today about 1 to 700,000 to 1 million,
corresponding to occult infections despite the viral genomic
diagnosis in blood bank.
The HCV identification thus had a major individual and
collective effect, transforming the diagnosis and prevention
of nosocomial or community-based risk, particularly among
drug-using patients.
Voxilaprevir); the polymerase inhibitors NS5B are in yellow (SOF =
Sofosbuvir; DSV = Dasabuvir) and the replication complex NS5A
inhibitors are in white (LDV = Ledipasvir; DCV = Daclatasvir; EBR
= Elabsvir; VEL = Velpatasvir; P = Pibentrasvir)
The major scientific steps
HCV life cycle
HCV is a small, enveloped, positive single-stranded RNA
virus belonging to the Flaviviridae family, genus Hepaci-
virus. The enveloped particles have an icosahedral diameter
of 56–65 nm [10], while the viral core is around 45 nm [11].
It is important to understand the key stages of the HCV viral
cycle in order to understand the mode of action of different
treatments even if the molecular mechanisms underlying
this cycle are not completely understood and remain
extremely complex. We have therefore selected important
steps in this cycle and their protein actors, in order to
introduce therapeutic objectives and the particular rela-
tionship of HCV with the liver.
The first step in the HCV replication cycle is its entry
into the cell through the interaction of its E1 and E2 surface
glycoproteins with the baso-lateral hepatocyte membrane, in
contact with the blood stream. HCV can be associated with
lipoproteins in the serum, thus escaping neutralizing anti-
bodies [12]. As many other viruses, the initiation of HCV
entry seems to utilize for attachment glycosaminoglycans
(GAGs) [13, 14]. The HCV particle interacting with

lipoprotein, it is more likely that the apolipoprotein E is
responsible for the interaction with GAGs [15]. Many
membrane molecules seem to be the target of the pathogen
and allow its entry, including ubiquitous CD81 (tetraspanin
family protein -TSPAN28) [14, 15], the LDL receptor,
claudin-1 (Cldn1) or occludin (OCLN) [16–18]. In vivo, its
entry into the cell is done in several steps: the envelope
glycoprotein E2 interacts with a co-receptor that is sca-
venger receptor B1 (SR-B1), and with CD81 [19]. The
interaction between CD81 and the E2 glycoprotein appears
to be essential for initiating the adsorption [12], then the
receptor complex with attached virion is moving to the tight
junction, where an interaction with proteins claudin-1 and
occluding set up. Finally, other cellular factors such as
Epidermal Growth Factor (EGF) receptor [20] and the
Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake
receptor [21] are likely involved in HCV entry. Subse-
quently, the virus is internalized in clathrin vesicles and
fused with early endosomes [22–25]. The acidification of
the vacuole allows the membrane fusion of the virus, the
virus capsid is then released and destroyed while the viral
RNA is released in the cytosol. Once in the cystosol, the
viral RNA is used for both processes the replication and the
polyprotein translation. The RNA translation into poly-
protein occurs in endoplasmic reticulum (ER) and is initi-
ated by binding of the 5′UTR IRES to the ribosome [26].
The primary translation product is ~3000 amino acid long
polyprotein precursor which contains structural and non-
structural proteins of HCV. Then, the polyprotein is cleaved
by host and viral proteases into three structural proteins
(Core protein, envelop proteins E1 and E2) as well as seven
non-structural proteins (p7, NS2, NS3, NS4A, NS4B,
NS5A, NS5B) of the viral replication machinery [12] and in
addition a Frameshift protein (F protein) or Alternate
reading frame protein (ARFP). The functions of ARFP in
the viral life cycle remain to be elucidated [27, 28] and
could modulate the dendritic cells function and stimulate the
T cell responses [29, 30].
The viral RNA will be replicated by the protein NS5B,
the RNA-dependent RNA polymerase (RdRp) containing
the GDD motif in its active site [31]. For HCV RNA
replication, the polarized positive HCV RNA genome
synthesizes a negative strand HCV RNA by the NS5B
RNA-dependent RNA polymerase. The newly synthesized
negative strand of HCV RNA may act as a template to
synthesize the positive strand of viral RNA [32–34].
After an accumulation of structural proteins and the viral
RNA in the cytosol, the morphogenesis of virions can start.
HCV needs a liver-specific microRNA named miR122 to
replicate properly. The latter recruits proteins in 5′ viral
RNAs, thus preventing their degradation by intracellular
exonucleases [35, 36].
S. Pol, S. Lagaye
The life cycle of HCV seems to be related to that of
lipoproteins: beyond its association with them to escape the
immune system in the blood and facilitate its entry into
hepatocytes, they are also necessary for its morphogenesis.
The Core protein, forming the viral capsid, will bind to
intracellular lipid droplets to initiate the virion morphogenesis.
The replication of the virus completely changes the distribu-
tion of intracellular lipid droplets: they are physiologically
distributed equitably throughout the cytosol of the hepato-
cytes but are found concentrated in the perinuclear domain
during the replication of the virus. In addition, apolipoproteins
A1, B, C1, C3, and E are found on the surface of the envelope
of viruses. Only Apo E seems strictly necessary for the via-
bility of virions. Finally, if one blocks certain proteins
necessary for the genesis of VLDL, such as MPT (micro-
somal triglyceride transfer protein), the virus can no longer
replicate. The NS5A protein plays an important role in the
assembly of the virus, in the lipid protein C-droplet stage. The
lipid-capsid combination will surround the freshly replicated
RNA and then bind with the other structural proteins of the
glycoprotein envelope (E1 and E2) derived from the endo-
plasmic reticulum [37–41]. After entering the cell, its repli-
cation and translation of its proteins, as well as the assembly
of its various components, the virion is ready to be exocyted
and to infect new cells [42].
Cloning and sequencing of HCV, pseudo-particles:
the understanding of HCV replication cycle
The HCV genome was identified in 1989 by cloning it from
infected chimpanzee, while in humans the amounts were too
low for detection [6]. The first complete full-length HCV
cDNA clone was constructed from the HCV strain H77
(genotype 1a). The HCV RNA transcribed from this clone,
then followed by several full-length HCV RNAs was found
to be infectious after intrahepatic injection in a chimpanzee.
The HCV viremia was detected at week 1 and increased
from 1 × 102 genomes/mL to 1 × 106 genomes/mL at week 8
[43, 44]. Since these HCV clones were found to replicate
inefficiently in vitro, this limitation was resolved by R.
Bartenschlager et al. when subgenomic HCV replicon,
cloned from the HCV genome was constructed after trans-
fection into the Huh7 cells [45]. Several studies demon-
strated that the virus and host factors were important for the
HCV replication in cells; some mutations in the wide-type
(wt) consensus sequence efficiently contributed to the
replication and the adaptation to the host cells but if these
replicons with adaptive mutations could replicate with a
high efficiency, they were not able to produce infectious
particles in vitro. Finally, a selectable HCV replicon was
constructed containing the full-length HCV cDNA of the
genotype 2a infectious clone JFH-1 (the only HCV strain
The remarkable history of the hepatitis C virus
reported to induce fulminant HCV-related hepatitis) and
was shown to produced infectious particles in vitro and
in vivo [46]. The most efficient construct is the genotype 2a/
2a clone which consists of J6CF and JFH-1 derived
sequence [47]. The HCV replicon is remarkably valuable
for studying HCV replication and for testing new antiviral
drugs. The HCV subgenomic replicons containing reporter
genes (luciferase, secreted alkaline phosphatase and chlor-
amphenicol transferase) facilitated the study of the HCV
infection. This high-throughput screening assay allowed the
visualization and tracking of the HCV replication complex
in living host cells without affecting HCV replication
[48, 49].
HCV pseudotyped particles were constructed with chi-
meric genes expressing HCV (genotype 1a) envelope E1
and E2 proteins (HCVpp) and the transmembrane and
cytoplasmic tail of vesicular stomatitis virus G protein.
These pseudotyped particles allowed a detailed study of the
role of HCV receptors in the early steps of HCV infection
(adsorption and viral entry) [50, 51] and for testing new
antiviral drugs [52]. All these major discoveries have been
previously detailed [26, 53].
Non-invasive tests of fibrosis improving screening
and individualizing therapies
Given their limited efficacy and their poor tolerance,
interferon-based therapies were restricted to patients with
significant fibrosis. The evaluation of hepatic lesions was
only performed by liver biopsy. This has been revolutio-
nized by the development of non-invasive fibrosis tests
evaluating both the necro-inflammation activity (A) and the
fibrosis stage according to different scoring system [54]. At
the same time blood tests (Fibrotest, Fibrometer, Hepascore,
FIB-4 or APRI) [55, 56] or morphological tests including
pulse elastometry [57, 58], which measures a shearing force
corresponding to the liver stiffness makes it possible. These
tools make it possible to evaluate F fibrosis on a conven-
tional Metavir scale of 0–4, where F0 and F1 correspond to
a null or minimal fibrosis as opposed to medium F2 fibrosis,
extensive F3 or cirrhotic F4 which justify not only a ther-
apeutic treatment but also a follow-up of the patients
because of the risks of hepatocellular carcinoma.
The polymorphism of IL28B
Well-established on-treatment and baseline predictors of
sustained virological response (SVR) to pegylated inter-
feron and ribavirin (PEG-IFN/RBV) in patients with
chronic hepatitis C virus (HCV) genotype 1 infection
include rapid virological response (RVR; undetectable HCV
RNA at week 4), low baseline viral load (<600,000 IU/mL),
non-black race, and absence of severe fibrosis or insulin
resistance [59, 60]. For some years, low serum levels of the
10 kDa interferon gamma-induced protein (IP-10) have also
been associated with a better PEG-IFN/RBV response [61].
Candidate genes have long been targeted to explain the
differences in host antiviral response, and it is now well
established that host genetics plays a role in the response to
IFN-based therapy in HCV infection [62]. Five GWAS
investigations described several single nucleotide poly-
morphisms (SNPs) in the IL28B gene region on chromo-
some 19 as being highly predictive of spontaneous
clearance of acute hepatitis C infection [62], response to
PEG-IFN α/RBV therapy in the general population as well
as in human immunodeficiency virus (HIV) co-infected
individuals and liver transplant recipients in whom both
donor and recipient IL28B haplotypes contribute to the
probability of treatment response [63, 64].
The GWAS data demonstrated an association between
variations at the IL28B gene locus and outcomes in HCV
infection, but did not identify a causal variant responsible
for these effects: the specific immunologic mechanisms
involved in HCV clearance associated with IL28B genotype
remain elusive and a functional link between IL28B geno-
type and liver cytokine expression has not been established
[65]. IL28B encodes for IFN- λ3 which belongs to the
family of type III IFNs; type III INFs effect their antiviral
activity by activating the JAK-STAT pathway, which leads
to the induction of IFN stimulated genes (ISGs) from
interferon stimulated response elements (ISREs) in the
nucleus [65]. Thus, it is involved in the T-cell adaptive
immune response [66] and IL28B has been associated with
increased CD8+ cytotoxic T cell responses. Interestingly, it
has been demonstrated that in non-responders, some
interferon-stimulated genes were upregulated before treat-
ment. In addition, minor alleles of IL28B polymorphisms
(i.e. rs8099917 G and rs12979860 T) have been associated
with reduced IL28B expression in peripheral blood mono-
nuclear cells [66]. Thus, IL28B genotypes may play a role in
viral containment, and it is suggested that IL28B poly-
morphisms associated with poor HCV clearance may
actually be protective against hepatic necro-inflammation
and fibrosis progression, particularly in patients with HCV
genotypes other than 1 [67].
A chronic infection with liver and extra-hepatic
consequences
The natural history of viral infection C is characterized by
hepatotropism and lymphotropism of the virus (Fig. 2).
Hepatotropism accounts for the risks of chronic hepatitis
(there is no risk of fulminant hepatitis outside the only strain
of genotype 2 at the origin of the first replicon) and of
cirrhosis and hepatocellular carcinoma like all chronic
hepatitis [68]. Lymphotropism is characterized by HCV

Fig. 2 The natural history of
HCV infection combining
hepatic and extra-hepatic
manifestations (which may
combine manifestations of
cryoglobulinemic vasculitis and
of chronic inflammation)
replication within B cells and explains the detection of
cryoglobulinemia in about half of infected patients. This
cryoglobulin is predominantly of type II associating a
monoclonal IgM contingent and a polyclonal IgG con-
tingent, and more rarely a type III cryoglobulinemia. It is a
protein complex associating the virus with antiviral anti-
bodies and rheumatoid factor that will be deposited in the
walls of small and medium-caliber vessels causing cryo-
globulinemic vasculitis responsible for cutaneous involve-
ment (purpura, necrotizing vasculitis), rheumatologic
(polyarthritis of the small joints), renal (membranoproli-
ferative glomerulonephritis), and neurological manifesta-
tions with frequent peripheral neuropathies and rarely
central attacks [69–71]. At most, the B lymphocyte infec-
tion can lead to a clonal selection responsible for lymphoma
predominantly Non-Hodgkin B-cell lymphoma (splenic
villous lymphoma, but sometimes more diffuse lymphomas)
[72, 73].
The chronic infection that occurs in three quarters of
infected subjects is also responsible for chronic inflamma-
tion that will lead to extra-hepatic manifestations associating
neurocognitive disorders, insulin resistance with a risk 1.5
times higher of diabetes, a risk two to three times higher of
cardio-, cerebro- or reno-vascular diseases and an increased
risk of extra-hepatic cancers [69–75]. These liver and extra-
hepatic events account for a ten-fold higher mortality in
patients with antibodies to HCV with detectable viral C
RNA compared to those without detectable HCV RNA or in
patients who have never met HCV [74, 75]. Extra-hepatic
mortality is twice as frequent in patients with active infection
as in patients without active viral infection C or without
prior HCV exposure. When HCV infection is confirmed, it is
important to evaluate the clinical consequences of hepatic
S. Pol, S. Lagaye
and extra-hepatic infections. The evaluation of hepatic
lesions was previously performed only on the basis of a liver
biopsy and has been revolutionized by the development of
non-invasive fibrosis tests (see above). Patients with “sig-
nificant” fibrosis (extensive F3 or cirrhotic F4) or even
intermediate (F2) but with hepatic co-morbidities justify not
only a priority therapeutic management and therefore a
virological cure, a hygiene and dietary education to reduce
chronic alcohol consumption, overweight or metabolic
syndrome (liver co-morbidities) but also a follow-up because
of the risk of occurrence of hepatocellular carcinoma,
admittedly reduced but not zero [68].
Thus, HCV infection is not only a hepatic infection but a
systemic disease [69–75] whose consequences are less
related to a direct toxicity of the virus than to immuno-
mediated mechanisms: chronic hepatitis is mainly related to
a destruction of hepatocytes by specific cytotoxic T lym-
phocytes recognizing the viral antigens expressed on the
surface of the cells.
In immunocompetent and immunocompromised patients
with little, or no intrahepatic damage, including inflamma-
tion, high levels of the HCV replication have been reported
[76]. In about 30% of HCV liver transplanted patients,
despite the high levels of HCV replication, a recurrent
hepatitis is developed one year after transplantation. How-
ever, high levels of an intrahepatic HCV replication are
usually tolerated by the host immune system. A lympho-
mononuclear infiltrate represented mainly by CD8+ T cells
is expected to play a major role in the viral containment,
though other subsets, such as CD4+ T and natural killer
(NK) cells, and regulatory T cells (Treg) are considered
[77]. The intrahepatic CD4+ and CD8+ T cells can recog-
nize HCV structural and nonstructural antigens [78].
The remarkable history of the hepatitis C virus
However, why in most patients the immune response cannot
resolve the infection, remains obscure. In fact, cytotoxic
CD8+ T cell-mediated killing could be blunt by a pre-
dominant Treg response [79].
The only chronic viral infection that is virologically
cured
The biology of HCV is simple with a positive-polarity HCV-
RNA that will be translated into a polyprotein that will be
split by a protease into different structural and non-structural
proteins. The NS3/4 protease, the NS5B polymerase are like
the key enzymes in viral replication as well as the NS5A
protein or replication complex which participates not only in
the replication of the viral RNA but also in the assembly of
the viral particles. The specific inhibition of these proteins
from the years 2005 allowed a control of the viral multi-
plication [80]. Viral replication and viral organogenesis are
exclusively cytoplasmic, which facilitates the targeting of
antiviral drugs. In contrast to HIV or hepatitis B virus
(HBV), there is no reservoir, no pro-viral DNA, no micro-
chromosome (HBV cccDNA) and no genomic integration.
This explains that one can obtain with the treatments a
virologic cure, the so-called SVR, defined by undetectable
HCV-RNA at 12 weeks after the infection or after the end
of the treatment which corresponds to a true virological
cure. HCV RNA undetectability in the serum is accom-
panied by undetectability in peripheral blood mononuclear
cells and in hepatocytes testifying to the complete and
lasting nature of virologic cure [81]. This cure is confirmed
by organ transplantation of infected subjects who have
benefited from effective treatment, unlike HBV for exam-
ple, transplantation (derogatory) of these organs, and
despite deep immunosuppression, does not lead to any
infection [82].
Clinico-biological benefits of virological cure and
reversibility of manifestations
Virologic cure is usually accompanied by clinical
improvement or even clinical cure of liver and extra-hepatic
manifestations [71, 75, 83–89]. This explains the expected
reduction in mortality from hepatic and extra-hepatic
impacts of chronic infection. As an example in the pro-
spective CIRVIR cirrhotic compensated cohort of ANRS-
INSERM, we observed a reduction in the risk of the HCC
occurrence at 3 and 5 years (13.6 20.6% versus 3.3% and
8.8% in cured patients, respectively) [90]; in cured patients,
HCC is observed only in cases of hepatic comorbidity
(metabolic syndrome, overweight, diabetes, alcohol abuse).
In addition to the reduced risk of HCC observed in cirrhotic
and non-cirrhotic patients, a virological healing also reduces
liver and overall mortality in patients [75, 91]. The
reduction in hepatic mortality is at least in part, related to
the ability to remodel fibrosis at all stages of the disease,
including the possibility of cirrhosis reversibility that con-
tributes to this reduction in mortality [85, 86]. Alongside the
significant reduction in liver risk (HCC and decompensa-
tion) in cirrhotic patients, there is a similar reduction in the
risk of bacterial infections and a reduction in vascular risks
(myocardial infarction, stroke or peripheral arterial disease)
with a reduction from 9.1 to 2.3% at 3 years and 12.3 versus
3.5% at 5 years in cirrhotic patients cured compared with
non-cured patients [92]. An extensive fibrosis or cirrhosis is
associated with an increased risk of carotid arteriosclerosis,
and oral antiviral therapies allow rapid reduction of carotid
intimal thickness [93].
Antiviral treatments
For more than 20 years Interferon for its antiviral and
immune-stimulatory properties has been used as the main
treatment for chronic infection with HCV [9, 59, 60].
Pegylation after 1997 resulted in weekly subcutaneous
rather than tri-weekly injections, and the addition of Riba-
virin, a nucleoside analogue, in the early 1990s significantly
increased the treatment efficacy [94]. Their limitations were
mainly poor clinical tolerance (flu-like syndrome, acuity of
dysimmunitary conditions, neurocognitive disorders aggra-
vated by Ribavirin) and biological (myelosuppression with
neutropenia and thrombocytopenia for Interferon, haemo-
lytic anemia for ribavirin). The SVR rate increased from
about 6% to at most 50% with 48-week treatments for the
most common genotypes 1 and 4 (24 weeks for genotypes 2
and 3 with a SVR rate of about 75%) [59]. A large number
of factors limited therapeutic efficacy, extensive fibrosis,
overweight, genotype 1, HIV-associated infection or insulin
resistance (see above). This limited efficiency and this dif-
ficult tolerance of interferon-based treatments explain that
availability of direct oral antivirals, specific inhibitors of
viral proteins, has been a real therapeutic revolution. The
first protease inhibitors, Telaprevir and Boceprevir, used
from 2011 to 2014, were combined with standard treatment
with pegylated interferon and ribavirin: they allowed a
halving of the treatment duration of genotypes 1 and 4
(24 weeks) and cured about three quarter of the patients [95]
but the safe issues remained. Since 2014, the combination
of 2–3 antivirals has been used to cure almost all patients
[80, 83, 84, 96–100]; the duration of the pangenotypic
treatments available since 2017 are 8–12 weeks with one to
three capsules per day (Fig. 1). The efficacy of these pan-
genotypic treatments (RVP > 97%) completely removed the
factors of poor response to treatment that can be given in all
clinical situations [96–100].
Therapeutic recommendations are today to treat all
patients infected with HCV by prioritizing those with

advanced liver diseases (fibrosis) or extra-hepatic (vasculi-
tis), risks of rapid progression of fibrosis (liver comorbid-
ities or transplants) or risks of community diffusion
[83, 84]. The benefit of these treatments is not only indi-
vidual but also collective by reducing the risk of infection
and infection/re-infection in risk communities such as men
who have sex with men (MSM) [101] or drug addicts
[102, 103].
The only limits that can be avoided today are the drug
interactions, the therapeutic observance and the rare side
effects associated with these treatments [104].
In summary, the history of HCV ends with this great
pangenotypic efficacy of multiple combinations, easy to use
8–12 weeks with one to three pill(s) per day and little
problem of tolerance. The virological cure allows a clinical
benefit with at worst a stabilization and at best a reversi-
bility of the clinico-biological manifestations. This explains
the short 30 years from the discovery of the virus to a policy
of elimination proposed by the WHO in 2016 [4].
HCV elimination
With the antiviral efficacy and good tolerance of pangen-
otypic drugs, the elimination (and not eradication in the
absence of an effective vaccine) is feasible provided that the
screening and access to care policies are improved. It is
considered that only 1% of the infected population world-
wide has been treated and cured [105]; this is, of course,
linked to the policy lack of screening and access to care but
also the drugs price. Of the approximately 5 million subjects
treated worldwide, probably 3 million have been treated
with low-cost generic treatments.
The provision of universal treatment and the simplifica-
tion of therapeutic strategies should make it possible to
hope for the effectiveness of elimination policies [106]
subject to: (1) improving screening policies through rapid
diagnostic orientation and “Point of Care” tests allowing, in
the different structures of care, to identify the infected
subjects with active infection and to initiate the treatments
(“test and treat” policy); (2) to open beyond the hospital and
specialized hepato-gastro-enterology, infectiologist or
internist structures an access to the prescription; (3)
“decentralize” patient care by relocating diagnostic and
treatment policies to sexual health structures, care facilities
in different communities, prisons, addiction centers,
maternity wards, migrant care centers, psychiatric services.
The provision of easy-to-use and low-cost treatment should
make this elimination possible.
The elimination as defined by WHO is feasible in Eur-
opean countries, and even planned for 2025 in France. It is
achieved in Iceland, expected in Egypt but seems difficult in
the US because of the epidemic HCV related to intravenous
drug use and very challenging in sub-Saharan Africa.
S. Pol, S. Lagaye
Compliance with ethical standards
Conflict of interest SP has received consulting and lecturing fees from
Bristol-Myers Squibb, Janssen, Gilead, MSD, Abbvie and grants from
Bristol-Myers Squibb, Gilead, Roche and MSD. The remaining author
declares that she has no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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